The 6p deletion syndrome: a new orofacial clefting syndrome and its implications for antenatal screening

Topping, Adam; Harris, Paul A.; Moss, A.L.H.

doi:10.1054/bjps.2001.3729

Cited by 22 publications

(18 citation statements)

References 18 publications

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“…Deafness is a common feature in 6p terminal deletions and, although specific genes have yet to be identified, 6p24 and 6p25 are possible loci for genes involved with hearing Davies et al, 1999b]. There is also evidence for a locus responsible for orofacial clefting at 6p24.3 Law et al, 1998;Topping et al, 2002]. Given the location of the breakpoint, our patient would be expected to be hemizygous for FKHL7 and AP-2a, as well as the suggested loci involved in hearing loss and orofacial clefting.…”

Section: Discussionmentioning

confidence: 82%

“…Six other patients with the same specific terminal breakpoint of 6p24 have been reported in the literature. Two patients were newborn Topping et al, 2002], and the remaining four patients reported had some degree of developmental disability. A 28-month-old female with communicating hydrocephalus had developmental delay evident by 6 months of age .…”

Section: Discussionmentioning

confidence: 98%

“…There have been approximately 30 reports of individuals with a deletion of the short arm of chromosome 6 Jalal et al, 1989;Zurcher et al, 1990;Palmer et al, 1991;Plaja et al, 1994;Alashari et al, 1995;Law et al, 1998;Davies et al, 1999a,b;Topping et al, 2002], making such a finding a relatively rare event. The 6p22-pter segment is the most commonly affected region, with breakpoints at 6p22.2, 6p23, 6p24.2, and 6p25.1 being relatively frequently encountered Davies et al, 1999b].…”

Section: Introductionmentioning

confidence: 99%

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Mild developmental delay in terminal chromosome 6p deletion

Chen

Cherry

Hahn

et al. 2004

American J of Med Genetics Pt A

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Deletions involving the short arm of chromosome 6 are relatively rare. Although features of this condition are variable, common findings include developmental delay, ocular abnormalities, hearing loss, and cardiac defects. In an effort to define further the clinical variability of this condition, we report a 6-year-old female with a de novo terminal deletion of chromosome 6 at band 6p24, with mild gross motor delays and normal cognition.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Mild developmental delay in terminal chromosome 6p deletion

Chen

Cherry

Hahn

et al. 2004

American J of Med Genetics Pt A

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“…The human gene encoding AP-2␣, TFAP2A, maps in close proximity to a region of chromosome 6p24 that is frequently involved in translocations and deletions associated with orofacial clefting (Davies et al, 1999a(Davies et al, ,b, 2004Topping et al, 2002;Schultz et al, 2004), raising the possibility that alterations in the long-range cis-regulatory sequences controlling TFAP2A expression might be responsible for congenital defects affecting human facial development. In the context of evolution, evidence from multiple species indicates that changes in the spatial and temporal regulation of the AP-2 family of genes, among others, might underlie the evolution of the vertebrate neural crest and, ultimately, the diversity of craniofacial skeleton (Meulemans and BronnerFraser, 2002;Holzschuh et al, 2003;Knight et al, 2003Knight et al, , 2005Luo et al, 2003;O'Brien et al, 2004).…”

Section: Regulation Of Tcfap2a In the Fnp And Lbm Are Controlled By Dmentioning

confidence: 99%

Frontal nasal prominence expression driven by Tcfap2a relies on a conserved binding site for STAT proteins

Donner

Williams

2006

Developmental Dynamics

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The AP-2 transcription factor family is linked with development of the head and limbs in both vertebrate and invertebrate species. Recent evidence has also implicated this gene family in the evolution of the neural crest in chordates, a critical step that allowed the development and elaboration of the vertebrate craniofacial skeleton. In mice, the inappropriate embryonic expression of one particular AP-2 gene, Tcfap2a, encoding AP-2␣, results in multiple developmental abnormalities, including craniofacial and limb defects. Thus, Tcfap2a provides a valuable genetic resource to analyze the regulatory hierarchy responsible for the evolution and development of the face and limbs. Previous studies have identified a 2-kilobase intronic region of both the mouse and human AP-2␣ locus that directs expression of a linked LacZ transgene to the facial processes and the distal mesenchyme of the limb bud in transgenic mice. Further analysis identified two highly conserved regions of ϳ200 -400 bp within this tissue-specific enhancer. We have now initiated a transgenic and biochemical analysis of the most important of these highly conserved regions. Our analysis indicates that although the sequences regulating face and limb expression have been integrated into a single enhancer, different cis-acting sequences ultimately control these two expression domains. Moreover, these studies demonstrate that a conserved STAT binding site provides a major contribution to the expression of Tcfap2a in the facial prominences. Developmental Dynamics 235: 1358 -1370, 2006.

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“…A null mutation of this gene in either mice or zebrafish results in severe craniofacial defects, hypoplasia of the neural crest-derived skeletal elements, and facial clefting (14,16,31,43). In addition, the human gene, TFAP2A, is located at 6p24 in a region that has chromosomal translocations and deletions associated with facial clefting (9)(10)(11)35). The Drosophila melanogaster genome contains one AP-2 family member, and mutation of this gene also gives rise to defects in formation of the head (15,22).…”

mentioning

confidence: 99%

Identification and Analysis of a Conserved Tcfap2a Intronic Enhancer Element Required for Expression in Facial and Limb Bud Mesenchyme

Feng

Huang

Zhang

et al. 2008

Molecular and Cellular Biology

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Tcfap2a, the gene encoding the mouse AP-2␣ transcription factor, is required for normal development of multiple structures during embryogenesis, including the face and limbs. Using comparative sequence analysis and transgenic-mouse experiments we have identified an intronic enhancer within this gene that directs expression to the face and limb mesenchyme. There are two conserved sequence blocks within this intron, and the larger of these directs tissue-specific activity and is found in all vertebrate Tcfap2a genes analyzed. To assess the role of the enhancer in regulating endogenous mouse Tcfap2a expression, we have deleted this cis-regulatory sequence from the genome. Loss of this element severely impairs Tcfap2a expression in the limb bud mesenchyme but generates only a modest reduction in the facial mesenchyme. The reduction in Tcfap2a transcription is accompanied by altered patterning of the forelimb, resulting in postaxial polydactyly. These results indicate that the major role for this enhancer resides within the limb bud, and it serves to maintain a level of Tcfap2a expression that limits the size of the hand plate and the associated number of digit primordia. The potential role of this cis-acting sequence in modeling the size and shape of the face and limbs during evolution is discussed.

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The 6p deletion syndrome: a new orofacial clefting syndrome and its implications for antenatal screening

Cited by 22 publications

References 18 publications

Mild developmental delay in terminal chromosome 6p deletion

Mild developmental delay in terminal chromosome 6p deletion

Frontal nasal prominence expression driven by Tcfap2a relies on a conserved binding site for STAT proteins

Identification and Analysis of a Conserved Tcfap2a Intronic Enhancer Element Required for Expression in Facial and Limb Bud Mesenchyme

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